title: Polymorphisms of Helicobacter pylori signaling pathway genes and gastric cancer risk in the European Prospective Investigation into Cancer-Eurgast cohort.
abstract: Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccharide and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while NFKB1 activates the transcription of pro-inflammatory cytokines to elicit an immune response. Single nucleotide polymorphisms (SNPs) in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1,284 matched controls from the European Prospective Investigation into Cancer cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log-additive model, we found a significant association between SNPs in CD14, NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant (p = 0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC (p = 0.0003) and CD14 with cardia GC (p = 0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results, we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC.
authors.affiliation: Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, Barcelona, 08908, Spain.
authors.forename: Osmel
authors.initials: O
authors.lastname: Companioni
authors.forename: Catalina
authors.initials: C
authors.lastname: Bonet
authors.forename: Xavier
authors.initials: X
authors.lastname: Muñoz
authors.forename: Elisabete
authors.initials: E
authors.lastname: Weiderpass
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.forename: Claudia
authors.initials: C
authors.lastname: Agnoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Boutron-Ruault
authors.forename: Antoine
authors.initials: A
authors.lastname: Racine
authors.forename: Françoise
authors.initials: F
authors.lastname: Clavel-Chapelon
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Neil
authors.initials: N
authors.lastname: Murphy
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Vergnaud
authors.forename: Antonia
authors.initials: A
authors.lastname: Trichopoulou
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Benetou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.forename: Dorthe
authors.initials: D
authors.lastname: Johansen
authors.forename: Björn
authors.initials: B
authors.lastname: Lindkvist
authors.forename: Mattias
authors.initials: M
authors.lastname: Johansson
authors.forename: Malin
authors.initials: M
authors.lastname: Sund
authors.forename: Eva
authors.initials: E
authors.lastname: Ardanaz
authors.forename: Emilio
authors.initials: E
authors.lastname: Sánchez-Cantalejo
authors.forename: Jose M
authors.initials: JM
authors.lastname: Huerta
authors.forename: Miren
authors.initials: M
authors.lastname: Dorronsoro
authors.forename: José
authors.initials: J
authors.lastname: Ramón Quirós
authors.forename: Anne
authors.initials: A
authors.lastname: Tjonneland
authors.forename: Lotte Maxild
authors.initials: LM
authors.lastname: Mortensen
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Cosmeri
authors.initials: C
authors.lastname: Rizzato
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno de Mesquita
authors.forename: Peter
authors.initials: P
authors.lastname: Siersema
authors.forename: Petra H M
authors.initials: PH
authors.lastname: Peeters
authors.forename: Mattijs E
authors.initials: ME
authors.lastname: Numans
authors.forename: Fatima
authors.initials: F
authors.lastname: Carneiro
authors.forename: Idlir
authors.initials: I
authors.lastname: Licaj
authors.forename: Heinz
authors.initials: H
authors.lastname: Freisling
authors.forename: Núria
authors.initials: N
authors.lastname: Sala
authors.forename: Carlos A
authors.initials: CA
authors.lastname: González
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology; D002299:Cardia / Q000473:pathology; D015331:Cohort Studies; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D016481:Helicobacter Infections / Q000150:complications* / Q000235:genetics; D016480:Helicobacter pylori / Q000235:genetics; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology
chemical_list: D018950:Lipopolysaccharide Receptors; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein
keywords: CD14; Helicobacter pylori; NOD2; gastric cancer; genetic susceptibility